Coronary artery bypass grafting was to be the surgical solution to coronary atherosclerosis. When percutaneous transluminal coronary angioplasty was introduced, it seemed to be the less-invasive alternative to coronary artery bypass grafting. Percutaneous transluminal coronary angioplasty with stenting then evolved to solve the issue of post-percutaneous transluminal coronary angioplasty artery collapse. The stents which have been used and are still being used in these procedures are small wire-mesh tubes that are commonly made of stainless steel or Nitinol. These devices are tightly secured on a balloon catheter and are gently guided to an area of occlusion within the coronary arteries. Once properly placed, the balloon is pressurized, resulting in the expansion of the stent and diseased blood vessel wall. The balloon catheter is then retracted, and the stent remains in place, providing mechanical support to keep the blood vessel open for increased blood flow to the heart. Various metal stents have been shown to reduce the restenosis rate compared with angioplasty alone. However, as in most fast-developing technology, percutaneous transluminal coronary angioplasty with stenting did not fully prevent the clinically challenging phenomenon of restenosis. This entails the narrowing of the stented coronary artery attributed to excessive smooth muscle cell proliferation (scarring) beneath the vessel's endothelium. Restenosis, which occurs in 25-30 percent of stented patients, is of no small concern to cardiology interventionists as well as to patients who have stents in situ or who are candidates for a stenting procedure. Among the factors contributing to restenosis is the biomechanical incompatibility of the high modulus of the metallic stent material and frequently acute geometries of their components contacting the soft luminal surface leading to complex traumatic events, including inflammation of cell lining of such surface. The biomechanical incompatibility was among the factors that prompted the pursuit of the study subject of the present invention, where a compliant polymer mantle is present between the high modulus stent construct and the soft luminal surface. For the past few years, the combination technology of devices in the form of stents and drugs capable of controlling one or more of the biological events contributing to restenosis led to the development of drug-eluting stents. These are, so far, based on metallic stent constructs with drug-bearing coatings. In effect, the drug-eluting stents were developed to eliminate (or at least diminish) the occurrence of restenosis in the coronary arteries after stenting. In very simple terms, a drug-eluting stent is one that is overcoated with a pharmaceutical agent that prevents or reduces the undesirable smooth muscle cell proliferation that occurs at the stent-delivery site, and thereby impedes recurrent stenosis. Recently, the drug-eluting stents have been introduced into clinical use. These stents were shown to reduce significantly the build up of tissue (in-stent restenosis) that occurs after the injurious effect of stent delivery. Commonly, metal stents are coated with a thin, usually nonabsorbable polymer that serves as the drug reservoir. In this way, a small amount of a highly potent drug can be delivered over a short period, usually 30 days. After the drug elutes from the thin polymer coating, the metal stent and the residual polymer coating remain in place. Over time, the permanent presence of the nonabsorbable device may lead to complications at the implant site.
Toward improving the biomechanical compatibility of the stents, while releasing a pharmaceutical agent, which can by themselves impede recurrent stenosis, a number of investigators of the prior art developed several forms of drug-containing absorbable and non-absorbable polymeric stents made of relatively lower modulus materials compared to metals. The rationale for nondegradable stents was the improved biocompatibility over the metal stent and convenient drug loading. Nonabsorbable polymers being investigated for stent use include polyethylene terephthalate, polyurethane, and polydimethyl siloxane. However, apart from the biomechanical compatibility, the nonabsorbable stents were inferior to their metallic counterparts in terms of their ease of deployment and retention of their physicomechanical properties at vascular sites. Meanwhile, the rationale for absorbable stents was support of body conduits only during their healing, delivery of drug from an internal reservoir to the surrounding tissue, without the need for surgery to remove the device. The most frequently used polymers for bioabsorbable stents are aliphatic polyesters, such as poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), and poly(ε-caprolactone) (PCL). Nonetheless, most of the stents described in the prior art are made of PLLA. An interesting design of the PLLA stent required expansion with a heated balloon, which represented an additional risk to the patient. Accordingly, this stent has not been commercialized. Another disadvantage of stents made of PLLA and similar polymers is their lack of visibility by X-ray radiography/fluoroscopy. This is a critical disadvantage as the physician relies on X-ray images to guide the stent to the location of the diseased vessel, as well as monitoring the performance of the stent after implantation. This disadvantage has contributed to the limited clinical and commercial acceptance of absorbable polymer stents.
It is well accepted that in-stent restenosis, the major adverse outcome after percutaneous coronary stent placement, can be successfully reduced by drug-eluting stents releasing cytostatic compounds. Numerous large clinical trials consistently revealed an impressive reduction of in-stent restenosis in de novo lesions by drug-eluting stents. However, in specific patient subsets, such as insulin-dependent diabetic subjects, or in challenging interventional scenarios, like bifurcation stenting, the rate of restenosis remains to be substantial at this point. Moreover, the outcome of treatment of in-stent restenosis with drug-eluting stents is currently not satisfactorily solved. Dose adjustments at the discretion of the interventional cardiologist to individualize the dosage of the compound on the drug-eluting stent may be desirable to enable an individual dose adjustment for specific lesion or patient subsets, e.g., higher rapamycin doses for diabetic patients. This provided a strong incentive to pursue a key segment of this invention where multiple bioactive agents are allowed to elute under controlled conditions, for instance, to inhibit smooth muscle cell proliferation and promote re-endothelialization.
Following the evolution of endovascular stent technology as noted above, it is obvious that (1) metallic stents suffer primarily from biomechanical compatibility as it relates to injuries to the vascular luminal wall; (2) coating the metallic stent with drug-bearing thin polymer film does reduce, to a limited extent, the effect of the biomechanical incompatibility of the stent—the coating does not totally eliminate the undesirable physical effect of the high modulus metal in contact with the vascular luminal wall; (3) the drug-eluting stents do not provide a precise control of the drug in concert with different prevailing critical biological events—this may be related, in part, to coating non-uniformity; and (4) use of absorbable stents as low modulus alternatives to metallic stents suffer primarily from their far-from-optimal ability to be deployed, inflated, and retain mechanical integrity at the application site compared to their metallic counterparts.
In an earlier disclosure by the present inventor (U.S. Pat. No. 6,797,485), a highly compliant, expandable, tubular mantle sleeve or cover made of absorbable, highly compliant polyaxial copolyester was described to be placed tightly outside an expandable metallic or polymeric stent so that under concentric irreversible expansion at the desired site of a treated biological conduit, such as blood vessel or an urethra, both components will simultaneously expand and the mantle provides a barrier between the inner wall of the conduit and the outer wall of the stent. In another aspect of that disclosure, the subject copolymers are used as a stretchable matrix of a fiber-reinforced cover sleeve, or mantle for a stent, wherein the fiber reinforcement is in the form of spirally coiled yarn (with and without crimping) woven, knitted, or braided construct. In effect, U.S. Pat. No. 6,797,485, describes a composite tubular cover or mantle for a stent, wherein the latter comprises a polymeric matrix reinforced with monofilament cross-spiral, wherein at least one of the matrix and reinforcement comprise an absorbable crystalline, monocentric, polyaxial copolyester and wherein the composite tubular cover or mantle can be microporous. However, both the tubular mantle and composite tubular mantle (1) are made independent of the stent and then placed in said stent; (2) are produced, in part, by casting a polymer solution on the mandrill (not the stent) and then allowed to dry; (3) are made to have much higher bulk density as compared to the electrospun mantle subject of this invention, which provides considerably higher compressibility and engineering compliance—this makes the electrospun mantle a more effective shock absorber between the high modulus metallic stent and the soft luminal wall, as compared to the mantle of U.S. Pat. No. 6,797,485 with its relatively high bulk density; and (4) have a much lower surface/volume ratio and practically one type of matrix that provides one diffusion pathway for drug elution as compared to the electrospun mantle of the present invention, which provides more than one type of matrices with high surface/volume ratio which makes it more suitable for more uniform and precise control of more than one drug at more than one diffusion rate and pathway.